Transition metal catalyst complexes play important roles in many areas of chemistry, including the preparation of polymers and pharmaceuticals. The properties of these catalyst complexes are recognized to be influenced by both the characteristics of the metal and those of the ligands associated with the metal atom. For example, structural features of the ligands can influence reaction rate, regioselectivity, and stereoselectivity. Bulky ligands can be expected to slow reaction rate; electron-withdrawing ligands, in coupling reactions, can be expected to slow oxidative addition to, and speed reductive elimination from, the metal center; and electron-rich ligands, in coupling reactions, conversely, can be expected to speed oxidative addition to, and slow reductive elimination from, the metal center.
In many cases, the oxidative addition step in the accepted mechanism of a coupling reaction is deemed to be rate limiting. Therefore, adjustments to the catalytic system as a whole that increase the rate of the oxidative addition step should increase overall reaction rate. Additionally, the rate of oxidative addition of a transition metal catalyst to the carbon-halogen bond of an aryl halide is known to decrease as the halide is varied from iodide to bromide to chloride, all other factors being equal. Because of this fact, the more stable, lower molecular weight, and arguably more easy to obtain, members of the set of reactive organic halides—the chlorides—are typically the poorest substrates for traditional transition metal catalyzed coupling reactions and the like. In many cases, the best halogen-containing substrates for transition metal catalyzed carbon-heteroatom and carbon-carbon bond forming reactions have been the iodides. Bromides have often been acceptable substrates, but have often required higher temperatures, longer reaction times, and have given lower yields of products.
Metal-catalyzed cross-coupling methodology to form carbon-carbon bonds has advanced organic synthesis. A., de Meijere, F. Diederich, Eds. Metal-Catalyzed Cross-Coupling Reactions, Vol. 2: Wiley-VCH, Weinheim, 2004. The Suzuki-Miyaura coupling is one of the preeminent methods for formation of carbon-carbon bonds and has been used in numerous synthetic ventures. N., Miyaura, Topics in Current Chem. 2002, 219, 11; and A. Suzuki, Organomet. Chem. 1999, 576, 147. In recent years, the palladium-catalyzed coupling of amines with aryl halides or sulfonates has been investigated. Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131; Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2047. Unfortunately, these methods are still subject to undesirable limitations, notwithstanding the improvements in the substrate scope of palladium-catalyzed C—N bond-forming reactions realized by using weak bases, such as potassium phosphate or cesium carbonate. Old, D. W. et al. J. Am. Chem. Soc. 1998, 120, 9722; Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359. Although the use of weak bases allows for the use of substrates containing ester, cyano, nitro and keto groups in the reaction, reactions of aryl substrates containing alcohol, phenol, or amide functional groups remain problematic. But see Harris, M. H. et al. Org. Lett. 2002, 4, 2885.
A new catalyst system that manifested high activity paired with extremely broad scope was recently reported. T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 4685; T. E. Barder, S. L. Buchwald Org. Lett. 2004, 6, 2649; S. D. Walker, T. E. Barder, J. R. Martinelli, S. L. Buchwald Angew. Chem. 2004, 116, 1907; and S. D. Walker, T. E. Barder, J. R. Martinelli, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871. In addition, a catalyst system based on PdCl2(CH3CN)2/3 which provides excellent reactivity in the copper-free Sonogashira coupling of aryl chlorides/tosylates and terminal alkynes has also been disclosed (for the structure of 3 see FIG. 1). D. Gelman, S. L. Buchwald Angew. Chem. 2003, 115, 6175; and D. Gelman, S. L. Buchwald Angew. Chem. Int. Ed. 2003, 42, 5993. However, this catalyst system was successful in coupling aryl alkynes only when the alkyne was added slowly over the course of the reaction. This fact is presumably due to competing non-productive oligomerization of the alkyne at higher concentrations in the presence of the catalyst.
There remains a need to develop reaction conditions for the coupling of water-soluble aryl chlorides and for the combination of difficult coupling partners in aqueous conditions. Additionally, compounds containing hydrophilic functional groups, which are insoluble in organic solvents and are present in many pharmaceutically interesting compounds, may be transformed using such a method, obviating the need for additional protection/deprotection steps. Further, conducting reactions in water is attractive since the aqueous components are easily separated from organic products. For reports of coupling reactions conducted in water or water/organic biphasic reaction solvents, see: C.-J. Li, T.-H. Chan. In Organic Reactions in Aqueous Media; Wiley: New York, 1997; Organic Synthesis in Water; P. A. Grieco, Ed.; Academic: Dordrecht, The Netherlands, 1997; Aqueous-Phase Organometallic Catalysis; B. Cornils, W. A. Herrmann, Eds., 2nd ed.; Wiley-VCH: Weinheim, 2004; K. H. Shaughnessy, R. B. DeVasher Curr. Org. Chem. 2005, 9, 585; N. E. Leadbeater Chem. Comm. 2005, (Advanced Article); B. Liang, M. Dai, J. Chen, Z. Yang J. Org. Chem. 2005, 70, 391; G. Zhang Synlett 2005, 4, 619; M. S. Mohamed Ahmed, A. Mori Tetrahedron 2004, 60, 9977; C. Wolf, R. Lerebours Org. Biomol. Chem. 2004, 2, 2161; and S. Bhattacharya, S. Sengupta Tetrahedron Lett. 2004, 45, 8733.
Very few examples have been reported concerning palladium-catalyzed cross-coupling reactions of hydrophilic aryl chlorides with aryl boronic acids using purely aqueous reaction conditions. See, for example, a NiCl2/dppe/trisulfonated triphenylphosphine system (J.-C. Galland, M. Savignac, J. P. Genet, Tetrahedron Lett. 1999, 40, 2323); using oxime-derived palladacycles (L. Botella, C. Najera, Angew. Chem. Int. Ed. 2002, 41, 179; and L. Botella Najera, J. Organomet. Chem. 2002, 663, 46); using di-2-pyridylmethylamine-based palladium complexes (C. Najera, J. Gil-Molto, S. Karlstrom, L. R. Falvello Org. Lett. 2003, 5, 1451); using palladium N-heterocyclic carbene complexes (I. Ozdemir, Y. Gok, N. Gurbuz, E. Cetinkaya, B. Cetinkaya Heterat. Chem. 2004, 15, 419; and I. Osdemir, S. Demir, S. Yaser, B. Cetinkaya, Appl. Organomet. Chem. 2005, 19, 55); or using TBAB-water mixtures (R. B. Bedford, M. E. Blake, C. P. Butts, D. Holder, Chem. Comm. 2003, 466). Several sulfonated phosphine derivatives have been prepared and used in cross-coupling reactions conducted in water or water/organic biphasic solvent systems. H. Gulyas, A. Szollosy, P. Szabo, P. Halmos, J. Bakos, Eur. J. Org. Chem. 2003, 2775; W. P. Mul, K. Ramkisoensing, P. C. J. Kamer, J. N. H. Reek, A. J. van der Linder, A. Marson, P. W. N. M. van Leeuwen, Adv. Syn. Catal. 2002, 344, 293; H. Gulyas, A. Szollosy, B. E. Hanson, J. Bakos, Tetrahedron Lett. 2002, 43, 2543; E. Schwab, S. Mecking, Organometallics 2001, 20, 5504; L. R. Moore, K. H. Shaughnessy Org. Lett. 2004, 6, 225; E. C. Western, J. R. Daft, E. M. Johnson II, P. M. Gannett, K. H. Shaughnessy, J. Org. Chem. 2003, 68, 6767; A. E. Sollewijn Gelpke, J. J. N. Veerman, M. S. Goedheijt, P. C. J. Kamer, P. W. N. M. van Leeuwen, H. Hiemstra Tetrahedron 1999, 55, 6657; H. Bahrmann, K. Bergrath, H.-J. Kleiner, P. Lappe, C. Naumann, D. Peters, D. Regnat, J. Organomet. Chem. 1996, 520, 97; J. P. Genet, A. Linquist, E. Blart, V. Mouries, M. Savignac, Tetrahedron Lett. 1995, 36, 1443. Shaughnessy reported that use of sterically demanding, water-soluble, alkylphosphine salts in the Suzuki-Miyaura, Sonogashira, and Heck coupling of unactivated aryl bromides provided excellent yields of products derived from carbon-carbon bond formation. R. B. DeVasher, L. R. Moore, K. H. Shaughnessy, J. Org. Chem. 2004, 69, 7919; and R. B. DeVasher, J. M. Spruell, D. A. Dixon, G. A. Broker, S. T. Griffin, R. D. Rogers, K. H. Shaughnessy, Organometallics 2005, 24, 962. Limitations to this methodology include a lengthy synthesis and poor thermal and air stability of the ligand. Furthermore, only a single example of a substituted aryl chloride was described. This was an activated aryl chloride (4-chlorobenzonitrile) that was combined with phenylboronic acid in a coupling that required 4 mol % of the palladium catalyst. Very recently, a Pd/glucosamine-based dicyclohexylarylphoshine catalyst was reported that displayed modest activity in Suzuki-Miyaura couplings of activated aryl chlorides when conducted in an water/toluene/ethanol solvent system. A. Konovets, A. Penciu, E. Framery, N. Percina, C. Goux-Henry, D. Sinou, Tetrahedron Lett. 2005, 46, 3205. This system was not reported to be general, and the ligand is difficult to prepare.